The present proposal seeks to clarify the role of aberrant Cu chemistry (peroxidation/nitration) in the pathogenesis of SOD1. One component will examine the abilities of FALS mutant SOD1, particularly enzyme with mutations involving crucial histidine, to bind Cu and to react with H202 and -OONO. A second components will determine whether experimentally mutated SOD1, lacking the capacity to bind Cu and encoding FALS mutations, can cause ALS-like motor neuron disease in mice. The third component of the study will operate under the assumption that, even if aberrant Cu chemistry is not the primary mechanism by which all FALS mutant SOD1 causes disease, some mutants do have enhanced peroxidase and nitration activities, and the level of these associated activities may modulate the severity of the disease.